EP1756279A1 - Procede de production d'acides l-amines a l'aide de bacteries coryneformes recombinantes avec regulateur asur a activite reduite - Google Patents

Procede de production d'acides l-amines a l'aide de bacteries coryneformes recombinantes avec regulateur asur a activite reduite

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Publication number
EP1756279A1
EP1756279A1 EP05700861A EP05700861A EP1756279A1 EP 1756279 A1 EP1756279 A1 EP 1756279A1 EP 05700861 A EP05700861 A EP 05700861A EP 05700861 A EP05700861 A EP 05700861A EP 1756279 A1 EP1756279 A1 EP 1756279A1
Authority
EP
European Patent Office
Prior art keywords
asur
methionine
amino acids
bacteria
gene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05700861A
Other languages
German (de)
English (en)
Inventor
Daniel Koch
Christian RÜCKERT
Jörn Kalinowski
Alfred Pühler
Brigitte Bathe
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Evonik Operations GmbH
Original Assignee
Degussa GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Degussa GmbH filed Critical Degussa GmbH
Publication of EP1756279A1 publication Critical patent/EP1756279A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/04—Alpha- or beta- amino acids
    • C12P13/12—Methionine; Cysteine; Cystine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/34—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Corynebacterium (G)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/74—Vectors or expression systems specially adapted for prokaryotic hosts other than E. coli, e.g. Lactobacillus, Micromonospora
    • C12N15/77—Vectors or expression systems specially adapted for prokaryotic hosts other than E. coli, e.g. Lactobacillus, Micromonospora for Corynebacterium; for Brevibacterium

Definitions

  • the invention relates to a process for the fermentative production of L-amino acids, in particular 5 L-methionine, using coryneform bacteria in which the asuR gene is weakened.
  • the asuR gene codes for the regulator AsuR.
  • Chemical compounds in particular L-0 amino acids, vitamins, nucleosides and nucleotides and D-amino acids, are used in human medicine, in the pharmaceutical industry, in cosmetics, in the food industry and in animal nutrition.
  • Process improvements can relate to fermentation-related measures such as stirring and supply of oxygen, or the composition of the nutrient media such as the sugar concentration during fermentation, or the processing into the product form by, for example, ion exchange chromatography or the intrinsic performance properties of the microorganism itself.
  • strains are obtained which are resistant to antimetabolites such as the lysine analogue S- (2-aminoethyl) cysteine or the methionine analogues ⁇ -methyl-methionine, ethionine, norleucine, N-acetylnorleucine, S-trifluoromethylhomocysteine, 2 -amino-5- Heprenoitklare, seleno-methionine, methionine sulfoximine, methoxine, 1-aminocyclopentane carboxylic acid or are auxotrophic for regulatory-important metabolites and produce L-amino acids.
  • antimetabolites such as the lysine analogue S- (2-aminoethyl) cysteine or the methionine analogues ⁇ -methyl-methionine, ethionine, norleucine, N-acetylnorleucine, S-trifluoromethylhomocy
  • the inventors have set themselves the task of providing new foundations for improved processes for the fermentative production of L-amino acids, in particular L-methionine, with coryneform bacteria.
  • one or more of the protein amino acids including their salts are selected from the group L-aspartic acid, L-asparagine, L-threonine, L-serine, L-
  • L-methionine is particularly preferred.
  • Proteinogenic amino acids are those
  • Amino acids that are found in natural proteins, i.e. in proteins from microorganisms, plants, animals and humans. They serve as structural units for proteins in which they are linked to one another via peptide bonds. If L-methionine or methionine are mentioned in the following, this also means the salts such as, for example, methionine hydrochloride or methionine sulfate.
  • the regulator AsuR is an activator of genes that are involved in the uptake and utilization of sulfur-containing compounds, in particular sulfonates. It is repressed by sulfate. AsuR also represses genes of cysteine biosynthesis. Cysteine biosynthesis is of great importance for methionine biosynthesis, since the sulfur required for the biosynthesis of methionine comes from sulfite and cysteine from cysteine biosynthesis.
  • the term “asuR” is derived from "alternate sulfur source utilization regulator".
  • Regulatory proteins that regulate the expression of other genes are those proteins that can bind to DNA, for example, by means of a specific protein structure called a helix-turn-helix motif and can thus either increase or decrease the transcription of other genes.
  • the weakening, in particular switching off, of the asuR gene coding for the regulator AsuR improves the production of L-methionine in the corresponding coryneform bacteria compared to the starting organisms without weakening or switching off this gene.
  • the invention relates to a process for the fermentative production of L-amino acids using coryneform bacteria, which in particular already produce L-amino acids and in which that for regulatory protein AsuR-encoding asuR gene is weakened, in particular switched off or is expressed at a low level.
  • This invention furthermore relates to a process for the fermentative production of L-amino acids, in which the following steps are carried out:
  • the coryneform bacteria used preferably produce L-amino acids, especially L-methionine, even before the asuR gene is weakened or switched off.
  • microorganisms preferably coryneform bacteria, produce L-amino acids, in particular L-methionine, in an improved manner after weakening, in particular switching off the regulator AsuR.
  • Corynebacterium glutamicum is state of the art and can be found in various patent applications and in the database of the National Center for Biotechnology Information (NCBI) and the National Library of Medicine (Bethesda, MD, USA).
  • NCBI National Center for Biotechnology Information
  • the nucleotide sequence of the gene coding for the regulator AsuR of Corynebacterium glutamicum can be found in patent application EP1108790 as sequence No. 12 and as sequence No. 1.
  • the nucleotide sequence is also stored in the database of the National Center for Biotechnology Information (NCBI) of the National Library of Medicin (Bethesda, MD, USA) under the accession number AX120096 and under the accession number AX120085. It can also be found under the accession number BX927148 from nucleotide 11177 to 10104 of the sequence given, the amino acid sequence of the associated protein is stored under the accession number CAF18575.
  • sequence described in the text passage coding for the gene asuR can be used according to the invention. Furthermore, alleles of the gene mentioned can be used, which result from the degeneracy of the genetic code or from function-neutral sense mutations (“sense mutations”).
  • weakening or “weakening” describes the reduction or elimination of the intracellular activity of one or more enzymes or proteins in a microorganism that are encoded by the corresponding DNA, for example by using a weak promoter or a gene or allele used which codes for a corresponding enzyme with a low activity or inactivates the corresponding gene or enzyme or protein and optionally combines these measures.
  • the attenuation measures generally reduce the activity or concentration of the corresponding protein to 0 to 75%, 0 to 50%, 0 to 25%, 0 to 10% or 0 to 5% of the activity or concentration of the wild-type protein, or the activity or concentration of the protein in the starting microorganism, is lowered.
  • the reduction in the protein concentration can be demonstrated by means of 1- and 2-dimensional protein gel separation and subsequent optical identification of the protein concentration using the appropriate evaluation software in the gel.
  • a common method for preparing the protein gels in coryneform bacteria and for identifying the proteins is that of Hermann et al. (Electrophoresis, 22: 1712-23 (2001)).
  • the protein concentration can also be determined by Western blot hybridization with an antibody specific for the protein to be detected (Sambrook et al., Molecular cloning: a laboratory manual. 2 nd Ed.
  • DNA-binding proteins can be measured by means of DNA band shift assays (also referred to as gel retardation) as described, for example, in the textbook “Bioanalytics” (Lotttechnisch / Zorbas, Spectrum Academic Publishing House Ginbh, Heidelberg, Germany, 1998) and by Wilson et al. (J. Bacteriol.
  • the microorganisms which are the subject of the present invention can produce amino acids from glucose, sucrose, lactose, fructose, maltose, molasses, starch, cellulose or from glycerol and ethanol. It can be Representatives of coryneform bacteria, in particular the genus Corynebacterium. In the genus Corynebacterium, the species Corynebacterium glutamicum should be mentioned in particular, which is known in the art for its ability to produce L-amino acids.
  • Suitable strains of the genus Corynebacterium, in particular of the species Corynebacterium glutamicum, are particularly the known wild-type strains
  • ATCC American Type Culture Collection
  • FERM National Institute of Advanced Industrial Science and Technology
  • ASIST Tsukuba Central 6, 1-1 -1 Higashi, Tsukuba Ibaraki, Japan The aforementioned strain of Corynebacterium thermoaminogenes (FERM BP-1539) is described in US-A-5,250,434.
  • the expression of the genes or the catalytic or regulatory properties of the enzyme proteins can be reduced or switched off. If necessary, both measures can be combined.
  • the gene expression can be reduced by appropriate culture management or by genetic modification (mutation) of the signal structures of the gene expression.
  • Signal structures of gene expression are, for example, repressor genes, activator genes, operators, promoters,
  • Attenuators riboso binding sites, the start codon and terminators.
  • the person skilled in the art finds information on this e.g. in patent application WO 96/15246, in Boyd and Murphy (Journal of Bacteriology 170: 5949-5952 (1988)), in Voskuil and Chambliss (Nucleic Acids Research 26: 3584-3590 (1998), in Patek et al.
  • An example of the targeted regulation of gene expression is the cloning of the gene to be weakened under the control of a promoter which can be induced by adding dosed amounts of IPTG (isopropyl - /? - D-thiogalactopyranoside) such as, for example, the trc promoter or the tac promoter.
  • IPTG isopropyl - /? - D-thiogalactopyranoside
  • vectors such as the Escherichia coli expression vector pXK99E (WO0226787; deposited according to the Budapest Treaty on July 31, 2001 in
  • DH5alpha / pXK99E as DSM14440 at the German Collection for Microorganisms and Cell Cultures (DSMZ, Braunschweig, Germany)) or pVWEx2 (Wendisch, Ph. D. thesis, reports from Anlagenstechnik Anlagenlich, Jül-3397, ISSN 0994-2952, Weglich, Germany ( 1997)), which enable IPTG-dependent expression of the cloned gene in Corynebacterium glutamicum.
  • Another method for specifically reducing> gene expression is the antisense technique, in which short oligodeoxyucleotides or vectors are brought into the target cells for the synthesis of longer antisense RNA.
  • the antisense RNA can bind to complementary sections of specific RNAs and reduce their stability or block translatability. An example of this can be found by the person skilled in the art in Srivastava et al. (Applied Environmental Microbiology 2000 Oct; 66 (10): 4366-4371).
  • Enzyme activity is spoken of missense mutations or nonsense mutations. Insertions or deletions of at least one base pair in a gene lead to frame shift mutations, in the result of which incorrect amino acids are incorporated or the translation terminates prematurely. Deletions from multiple codons typically result in complete loss of enzyme activity. Instructions for generating such mutations are state of the art and can be found in well-known textbooks of genetics and molecular biology such as the textbook by Knippers ("Molecular Genetics", 6th edition, Georg Thieme Verlag, Stuttgart, Germany, 1995), that of Winnacker (“ Gene and Clones “, VCH Verlagsgesellschaft, Weinheim, Germany, 1990) or that of Hagemann (“Institute Genetik “, Gustav Fischer Verlag, Stuttgart, 1986).
  • a central part of the coding region of the gene of interest is cloned into a plasmid vector which can replicate in a host (typically E. coli) but not in C. glutamicum.
  • vectors are PSUP301 (Simon et al., Bio / Technology 1, 784-791 (1983)), pKl ⁇ mob, pKl9mob, pKl ⁇ mobsacB or pKl9mobsacB (Schäfer et al., Gene 145, 69-73 (1994)), pGEM- T (Promega Corporation, Madison, WI, USA), pCR2.1-TOPO (Invitrogen, Groningen, The Netherlands; Shu an (1994).
  • the invention also relates to vectors which contain at least 15, preferably 25 successive nucleotides of the central part of the coding region of the gene asuR.
  • a mutation such as, for example, a deletion, insertion or base exchange in the gene of interest is produced in vitro.
  • the allele produced is in turn cloned into a vector which is not replicative for C. glutamicum and then cloned by Transformation or conjugation into the desired host of C. glutamicum after homologous recombination by means of a first, integration-causing "cross-over” event and a suitable second, excision-causing "cross-over” event in the target gene or in the
  • the target sequence is achieved by inserting the mutation or the allele.
  • a deletion, insertion or base exchange can be incorporated into one or more of the genes selected from the group yaeC, abc and yaeE.
  • L-amino acids in addition to the weakening of the regulator AsuR, one or more enzymes of the respective biosynthetic pathway, glycolysis, anaplerotic, the citric acid cycle, the pentose phosphate cycle, the amino acid export and possibly regulatory Either to amplify proteins, in particular to overexpress them, or to weaken them, in particular to switch them off or to reduce expression.
  • amplification or “amplification” describes the increase in the intracellular activity or concentration of one or more enzymes or proteins in a microorganism that are encoded by the corresponding DNA, for example by changing the number of copies of the gene or Genes increased, a strong promoter or a gene or all! used, which codes for a corresponding enzyme or protein with a high activity and optionally combines these measures.
  • the measures of enhancement in particular overexpression, generally reduce the activity or concentration of the corresponding protein by at least 10%, 25%, 50%, 75%, 100%, 150%, 200%, 300%, 400% or 500% , up to 1000% or 2000% based on that of the wild type Protein or the activity or concentration of the protein in the starting microorganism increased.
  • Endogenous genes or “endogenous nucleotide sequences” means the genes or nucleotide sequences present in the population of a species.
  • genes selected from the group of genes or alleles of methionine production can be amplified, in particular overexpressed, for the production of L-methionine.
  • Genes or alleles of methionine production are understood to mean all, preferably endogenous, open reading frames, genes or alleles, the strengthening / overexpression of which can bring about an improvement in methionine production.
  • genes or alleles include the following open reading frames, genes or alleles: accBC, accDA, aecD, cstA, cysD, cysE, cysH, cysK, cysN, cysQ, dps, eno, fda, gap, gap2, gdh, gnd, glyA, hom, hom FBR , lysC, lysC FBR , metA, metB, metE, metH, metY, msiK, opcA, oxyR, ppc, ppc FBR , pgk, pknA, pknB, pknD, pknG, ppsA, ptsH, ptsl, ptsM, pyc, pyc P458S, sigC, sigD, sigE, sigH, sig
  • L-methionine in addition to the weakening of the regulator AsuR, to simultaneously weaken, in particular switch off, one or more of the genes selected from the group of genes or alleles which are not essential for growth or methionine production or decrease expression.
  • genes or alleles include the following open reading frames, genes or alleles: brnQ, ccpAl, ccpA2, citA, citB, citE, ddh, gluA, gluB, gluC, gluD, luxR, luxS, lysRl, lysR2, lysR3, menE, ' metD, etK , pck, pgi, poxB and zwa2. These are summarized and explained in Table 2. Table 2
  • microorganisms produced according to the invention are also a subject of the invention and can be cultured continuously or batchwise in the batch process (batch cultivation) or in the fed batch (feed process) or repeated fed batch process (repetitive feed process) for the purpose of producing L-amino acids.
  • the culture medium to be used must meet the requirements of the respective strains in a suitable manner. Descriptions of culture media of various microorganisms are contained in the manual "Manual of Methods for General Bacteriology” of the American Society for Bacteriology (Washington D.C., USA, 1981).
  • Sugar and carbohydrates such as e.g. Glucose, sucrose, lactose, fructose, maltose, molasses, starch and cellulose, oils and fats such as e.g. Soybean oil, sunflower oil, peanut oil and coconut fat, fatty acids. such as. Palmitic acid, stearic acid and linoleic acid, alcohols such as e.g. Glycerin and ethanol and organic
  • Acids such as Acetic acid can be used. These substances can be used individually or as a mixture.
  • Organic nitrogen-containing compounds such as peptones, yeast extract, meat extract, malt extract, corn steep liquor, soybean meal and urea or inorganic compounds such as ammonium sulfate, ammonium chloride, ammonium phosphate, ammonium carbonate and ammonium nitrate can be used as the nitrogen source.
  • the nitrogen sources can be used individually or as a mixture.
  • Potassium dihydrogen phosphate or dipotassium hydrogen phosphate or the corresponding sodium-containing salts can be used.
  • the culture medium must also contain salts of metals such as e.g. Magnesium sulfate or iron sulfate, which are necessary for growth. After all, essential
  • Growth substances such as amino acids and vitamins can be used in addition to the substances mentioned above.
  • Suitable precursors can also be added to the culture medium.
  • the feedstocks mentioned can be used for culture in the form of a added one-off approach or added in a suitable manner during cultivation.
  • Basic compounds such as sodium hydroxide, potassium hydroxide, ammonia or ammonia water or acidic compounds such as phosphoric acid or sulfuric acid are used in a suitable manner to control the pH of the culture.
  • Anti-foam agents such as e.g. Fatty acid polyglycol esters are used.
  • suitable 'selectively acting substances such as e.g.
  • Antibiotics are added.
  • oxygen or gas mixtures containing oxygen e.g. Air entered the culture.
  • the temperature of the culture is usually 20 ° C to 45 ° C and preferably 25 ° C to 40 ° C.
  • the culture is continued until a maximum of the desired product has formed. This goal is usually achieved within 10 hours to 160 hours.
  • Combinations thereof can be improved by at least 0.5%, at least 1% or at least 2%.
  • the method according to the invention serves for the fermentative production of L-methionine.
  • the concentration of L-methionine in the end product can optionally be adjusted to the desired value by adding L-methionine.

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Abstract

L'invention concerne un procédé de production d'acides L-aminés, en particulier de L-méthionine, par fermentation. Selon ledit procédé, les bactéries corynéformes produisant les acides L-aminés souhaités sont fermentées et le régulateur AsuR est affaiblit, en particulier désactivé ou exprimé à un faible niveau. Cette invention concerne également ces microorganismes recombinants.
EP05700861A 2004-02-27 2005-01-13 Procede de production d'acides l-amines a l'aide de bacteries coryneformes recombinantes avec regulateur asur a activite reduite Withdrawn EP1756279A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE200410009453 DE102004009453A1 (de) 2004-02-27 2004-02-27 Verfahren zur Herstellung von L-Aminosäuren unter Verwendung von coryneformen Bakterien
PCT/EP2005/000243 WO2005083082A1 (fr) 2004-02-27 2005-01-13 Procede de production d'acides l-amines a l'aide de bacteries coryneformes recombinantes avec regulateur asur a activite reduite

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EP1756279A1 true EP1756279A1 (fr) 2007-02-28

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Country Link
EP (1) EP1756279A1 (fr)
CN (1) CN1922322A (fr)
DE (1) DE102004009453A1 (fr)
WO (1) WO2005083082A1 (fr)

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JP2009501550A (ja) * 2005-07-18 2009-01-22 ビーエーエスエフ ソシエタス・ヨーロピア メチオニン生産組換え微生物
CN101164694A (zh) 2006-10-20 2008-04-23 德古萨股份公司 用于催化气相氧化的混合氧化物催化剂
DE102006054202A1 (de) * 2006-11-17 2008-05-21 Evonik Degussa Gmbh Allele des oxyR-Gens aus coryneformen Bakterien
RU2009134794A (ru) * 2007-02-19 2011-03-27 Эвоник Дегусса ГмБх (DE) Способ получения метионина с использованием коринебактерий посредством свехэкспрессии ферментов пентозофосфатного пути
KR101756338B1 (ko) * 2016-01-15 2017-07-10 고려대학교 산학협력단 L-시스테인 생산용 변이미생물 및 이를 이용한 l-시스테인의 제조방법
JP7074133B2 (ja) * 2016-10-26 2022-05-24 味の素株式会社 目的物質の製造方法
CN116731950A (zh) * 2023-08-10 2023-09-12 中国科学院天津工业生物技术研究所 谷氨酸棒杆菌抗逆工程菌及其在生产酸性生物基化学品中应用

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JP4623825B2 (ja) * 1999-12-16 2011-02-02 協和発酵バイオ株式会社 新規ポリヌクレオチド
DE10126164A1 (de) * 2001-05-30 2002-12-05 Degussa Für das metD-gen kodierende Nukleotidsequenzen
DE10128510A1 (de) * 2001-06-13 2002-12-19 Degussa Methode zur Fermentationskontrolle

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CN1922322A (zh) 2007-02-28
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